Esophageal Cancer Treatment–for health professionals (PDQ®)

General Information About Esophageal Cancer

Incidence and Mortality

Estimated new cases and deaths from esophageal cancer in the United States in 2015:[1]

New cases: 16,980.

Deaths: 15,590.

The incidence of esophageal cancer has risen in recent decades, coinciding with
a shift in histologic type and primary tumor location.[2,3] Adenocarcinoma of
the esophagus is now more prevalent than squamous cell carcinoma in the United
States and western Europe, with most tumors located in the distal esophagus.
The cause for the rising incidence and demographic alterations is unknown.

Risk Factors and Survival

While risk factors for squamous cell carcinoma of the esophagus have been
identified (e.g., tobacco, alcohol, diet), the risk factors associated with
esophageal adenocarcinoma are less clear.[3] The presence of Barrett
esophagus is associated with an increased risk of developing adenocarcinoma of
the esophagus, and chronic reflux is considered the predominant cause of
Barrett metaplasia. The results of a population-based, case-controlled study
from Sweden strongly suggest that symptomatic gastroesophageal reflux is a risk
factor for esophageal adenocarcinoma. The frequency, severity, and duration of
reflux symptoms were positively correlated with increased risk of esophageal
adenocarcinoma.[4]

Esophageal cancer is a treatable disease, but it is rarely curable. The overall
5-year survival rate in patients amenable to definitive treatment ranges from 5% to 30%.
The occasional patient with very early disease has a better chance of survival.
Patients with severe dysplasia in distal esophageal Barrett mucosa often have
in situ or even invasive cancer within the dysplastic area. Following
resection, these patients usually have excellent prognoses.

Diagnostics for Staging

One of the major difficulties in allocating and comparing treatment modalities
for patients with esophageal cancer is the lack of precise preoperative
staging. Standard noninvasive staging modalities include computed tomography
(CT) of the chest and abdomen and endoscopic ultrasound (EUS). The overall
tumor depth staging accuracy of EUS is 85% to 90%, as compared with 50% to 80%
for CT; the accuracy of regional nodal staging is 70% to 80% for EUS and 50% to
70% for CT.[7,8] EUS-guided fine-needle aspiration (FNA) for lymph node
staging is under prospective evaluation; one retrospective series reported a
93% sensitivity and 100% specificity of regional nodal staging with EUS-FNA.[9] Thoracoscopy and
laparoscopy have been used in esophageal cancer staging at some surgical
centers.[10-12] An intergroup trial reported an increase in positive lymph node detection to 56% of 107 evaluable patients using thoracoscopy/laparoscopy, from 41% (using noninvasive staging tests, e.g., CT, magnetic resonance imaging, EUS) with no major complications or deaths.[13] Noninvasive positron emission tomography using the
radiolabeled glucose analog 18-F-fluorodeoxy-D-glucose for preoperative
staging of esophageal cancer is under clinical evaluation and may be useful in
detecting stage IV disease.[14-17]

Cellular Classification of Esophageal Cancer

Fewer than 50% of esophageal cancers are squamous cell carcinomas.
Adenocarcinomas, typically arising in Barrett esophagus, account for at least
50% of malignant lesions, and the incidence of this histology appears to be
rising. Barrett esophagus contains glandular epithelium cephalad to the
esophagogastric junction.

b(1) At least maximal dimension of the tumor must be recorded, and (2) multiple tumors require the T(m) suffix.

cHigh-grade dysplasia includes all noninvasive neoplastic epithelia that was formerly called carcinoma in situ, a diagnosis that is no longer used for columnar mucosae anywhere in the gastrointestinal tract.

bOr mixed histology, including a squamous component or not otherwise specified.

cLocation of the primary cancer site is defined by the position of the upper (proximal) edge of the tumor in the esophagus.

Stage

T

N

M

Grade

Tumor Locationc

0

Tis (HGD)

N0

M0

1, X

Any

IA

T1

N0

M0

1, X

Any

IB

T1

N0

M0

2–3

Any

T2–3

N0

M0

1, X

Lower, X

IIA

T2–3

N0

M0

1, X

Upper, middle

T2–3

N0

M0

2–3

Lower, X

IIB

T2–3

N0

M0

2–3

Upper, middle

T1–2

N1

M0

Any

Any

IIIA

T1–2

N2

M0

Any

Any

T3

N1

M0

Any

Any

T4a

N0

M0

Any

Any

IIIB

T3

N2

M0

Any

Any

IIIC

T4a

N1–2

M0

Any

Any

T4b

Any

M0

Any

Any

Any

N3

M0

Any

Any

IV

Any

Any

M1

Any

Any

Adenocarcinoma

Stage

T

N

M

Grade

0

Tis (HGD)

N0

M0

1, X

IA

T1

N0

M0

1–2, X

IB

T1

N0

M0

3

T2

N0

M0

1–2, X

IIA

T2

N0

M0

3

IIB

T3

N0

M0

Any

T1–2

N1

M0

Any

IIIA

T1–2

N2

M0

Any

T3

N1

M0

Any

T4a

N0

M0

Any

IIIB

T3

N2

M0

Any

IIIC

T4a

N1–2

M0

Any

T4b

Any

M0

Any

Any

N3

M0

Any

IV

Any

Any

M1

Any

The current staging system for esophageal cancer is based largely on
retrospective data from the Japanese Committee for Registration of Esophageal
Carcinoma. It is most applicable to patients with squamous cell carcinomas of
the upper third and middle third of the esophagus, as opposed to the increasingly
common distal esophageal and gastroesophageal junction adenocarcinomas.[2] In
particular, the classification of involved abdominal lymph nodes as M1 disease
has been criticized. The presence of positive abdominal lymph nodes does not
appear to carry as grave a prognosis as metastases to distant organs.[3]
Patients with regional and/or celiac axis lymphadenopathy should not
necessarily be considered to have unresectable disease caused by metastases.
Complete resection of the primary tumor and appropriate lymphadenectomy should
be attempted when possible.

Treatment Option Overview for Esophageal Cancer

The prevalence of Barrett metaplasia in adenocarcinoma of the esophagus
suggests that Barrett esophagus is a premalignant condition. Strong
consideration should be given to resection in patients with high-grade
dysplasia in the setting of Barrett metaplasia. Endoscopic surveillance of
patients with Barrett metaplasia may detect adenocarcinoma at an earlier
stage more amenable to curative resection.[1] The survival rate of patients
with esophageal cancer is poor. Asymptomatic small tumors confined to the
esophageal mucosa or submucosa are detected only by chance. Surgery is the
treatment of choice for these small tumors. Once symptoms are present
(e.g., dysphagia, in most cases), esophageal cancers have usually invaded
the muscularis propria or beyond and may have metastasized to lymph nodes or
other organs.

In the presence of complete esophageal obstruction without clinical evidence
of systemic metastasis, surgical excision of the tumor with mobilization of the
stomach to replace the esophagus has been the traditional means of relieving
the dysphagia. In the United States, the median age of patients who present
with esophageal cancer is 67 years.[2] The results of a retrospective
review of 505 consecutive patients who were operated on by a single surgical
team over 17 years found no difference in the perioperative mortality, median
survival, or palliative benefit of esophagectomy on dysphagia when the group of
patients older than 70 years were compared to their younger peers.[3][Levels of
evidence: 3iiA and 3iiB] All of the patients in this series were selected for
surgery on the basis of potential operative risk. Age alone should not determine
therapy for patients with potentially resectable disease.

The optimal surgical procedure is controversial. One approach
advocates transhiatal esophagectomy with anastomosis of the stomach to the
cervical esophagus. A second approach advocates abdominal mobilization of the
stomach and transthoracic excision of the esophagus with anastomosis of the
stomach to the upper thoracic esophagus or the cervical esophagus. One study concluded that transhiatal esophagectomy was associated with lower morbidity than transthoracic esophagectomy with extended en bloc lymphadenectomy; however, median overall disease-free and quality-adjusted survival did not differ significantly.[4] Similarly, no differences in long-term quality of life (QOL) using validated QOL instruments have been reported.[5] In patients
with partial esophageal obstruction, dysphagia may, at times, be relieved by
placement of an expandable metallic stent [6] or by radiation therapy if the
patient has disseminated disease or is not a candidate for surgery.
Alternative methods of relieving dysphagia have been reported, including laser
therapy and electrocoagulation to destroy intraluminal tumor.[7-10]

Surgical treatment of resectable esophageal cancers results in 5-year survival
rates of 5% to 30%, with higher survival rates in patients with early-stage
cancers. This is associated with a less than 10% operative mortality rate.[11]
In an attempt to avoid this perioperative mortality and to relieve dysphagia,
definitive radiation therapy in combination with chemotherapy has been studied.
A Radiation Therapy Oncology Group randomized trial (RTOG-8501) of chemotherapy and radiation therapy versus radiation therapy
alone resulted in an improvement in 5-year survival for the combined modality
group (27% vs. 0%).[12][Level of evidence: 1iiA] An eight-year follow-up of this trial
demonstrated an overall survival (OS) rate of 22% for patients receiving
chemoradiation therapy.[12] An Eastern Cooperative Oncology Group trial (EST-1282) of 135
patients showed that chemotherapy plus radiation provided a better 2-year
survival rate than radiation therapy alone,[13] which was similar to that shown in the
Intergroup trial.[12][Level of evidence: 1iiA] In an attempt to improve upon the results
of RTOG-8501, Intergroup-0123 (RTOG-9405) randomly assigned 236 patients with
localized esophageal tumors to chemoradiation with high-dose radiation therapy
(64.8 Gy) and four monthly cycles of fluorouracil (5-FU) and cisplatin versus conventional-dose radiation therapy (50.4 Gy) and the same chemotherapy schedule.[14]
Although originally designed to accrue 298 patients, this trial was closed in 1999 after a planned interim analysis showed that it was statistically unlikely that there would be any advantage to using high-dose radiation. At 2 years' median follow-up, no statistical differences were observed between the high-dose and
conventional-dose radiation therapy arms in median survival (13 months vs.
18 months), 2-year survival (31% vs. 40%), or local/regional failures (56%
vs. 52%).[14][Level of evidence: 1iiA]

Preoperative Chemoradiation Therapy

Chemoradiation followed by surgery is a standard treatment option for patients with stages IB, II, III, and IVA esophageal cancer, based on the results of several randomized trials.

The ongoing CROSS study randomly assigned 366 patients with resectable esophageal or junctional cancers to receive either surgery alone or weekly administration of carboplatin (dose titrated to achieve an AUC [area under the curve] of 2 mg/mL/minute) and paclitaxel (50 mg/m2 of BSA [body surface area]) and concurrent radiation therapy (41.4 Gy in 23 fractions) administered over 5 weeks.[15][Level of evidence: 1iiA] The majority of the patients enrolled in the study have adenocarcinoma (75%).

With a median follow-up of 45 months, preoperative chemoradiation was found to improve median OS from 24 months in the surgery-alone group to 49.4 months (hazard ratio [HR], 0.657; 95% confidence interval [CI], 0.495–0.871, P = .003). Additionally, preoperative chemoradiation improved the rate of R0 resections (R0 is defined as complete resection with no tumor within 1 mm of resection margins, 92% vs. 69%, P < .001). A complete pathologic response was achieved in 29% of patients who underwent resection after chemoradiation therapy. Postoperative complications and in-hospital mortality were equivalent in both groups. The most common hematologic side effects in the chemoradiation group were leukopenia (6%) and neutropenia (2%). The most common nonhematologic side effects were anorexia (5%) and fatigue (3%).[15]

Other phase III trials have compared preoperative concurrent chemoradiation therapy to
surgery alone for patients with esophageal cancer.[15-19][Level of evidence: 1iiA] A multicenter
prospective randomized trial in which preoperative combined chemotherapy
(i.e., cisplatin) and radiation therapy (37 Gy in 3.7 Gy fractions) followed by
surgery was compared to surgery alone in patients with squamous cell carcinoma
showed no improvement in OS and a significantly higher
postoperative mortality (12% vs. 4%) in the combined modality arm.[16] In
patients with adenocarcinoma of the esophagus, a single-institution phase III
trial demonstrated a modest survival benefit (16 months vs. 11 months) for
patients treated with induction chemoradiation therapy consisting of 5-FU,
cisplatin, and 40 Gy (2.67 Gy fractions) plus surgery over resection
alone.[17] A subsequent single-institution trial randomly assigned patients (75% with
adenocarcinoma) to 5-FU, cisplatin, vinblastine, and radiation
therapy (1.5 Gy twice daily to a total of 45 Gy) plus resection versus
esophagectomy alone.[18] At a median follow-up of more than 8 years, there was no
significant difference between the surgery alone and combined modality therapy
with respect to median survival (17.6 months vs. 16.9 months), OS (16% vs. 30% at 3 years), or disease-free survival (16% vs. 28%
at 3 years). An Intergroup trial (CALGB-9781) planned to randomly assign 475 patients with resectable squamous cell or adenocarcinoma of the thoracic esophagus to treatment with preoperative chemoradiation therapy (5-FU, cisplatin, and 50.4 Gy) followed by esophagectomy and nodal dissection or surgery alone.[19][Level of evidence: 1iiA] The trial was closed as a result of poor patient accrual; however, the results of the 56 enrolled patients, with a median follow-up of 6 years, were reported. The median survival was 4.48 years (95% CI, 2.4 years to not estimable) for trimodality therapy versus 1.79 years (95% CI, 1.41–2.59 years) for surgery alone (P = .002), with 5-year OS of 39% (95% CI, 21%–57%) versus 16% (95% CI, 5%–33%) for trimodality therapy versus surgery alone.

A phase III German trial also compared induction chemotherapy (three courses of bolus 5-FU, leucovorin, etoposide, and cisplatin) followed by chemoradiation therapy (cisplatin, etoposide, and 40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiation therapy (at least 65 Gy) without surgery (arm B) for patients with T3 or T4 squamous cell carcinoma of the esophagus.[20][Level of evidence: 1iiA] OS was the primary outcome. The analysis of 172 eligible, randomly assigned patients showed that OS at 2 years was not statistically significantly different between the two treatment groups (arm A: 39.9%; 95% CI, 29.4%–50.4%; arm B: 35.4%; 95% CI, 25.2%–45.6%; log-rank test for equivalence with 0.15, P < .007). Local progression-free survival (PFS) was higher in the surgery group (2-year PFS, 64.3%; 95% CI, 52.1%–76.5%) than in the chemoradiation therapy group (2-year PFS, 40.7%; 95% CI, 28.9%–52.5%; HR for arm B vs. arm A, 2.1; 95% CI, 1.3–3.5; P < .003). Treatment-related mortality was higher in the surgery group compared with the chemoradiation therapy group (12.8% vs. 3.5%, respectively; P < .03).

Preoperative Chemotherapy Alone

The effects of preoperative chemotherapy are being evaluated in randomized trials, as was done in the NCT00525785 trial.[21,22][Level of evidence: 1iiA]. An Intergroup trial randomly assigned 440 patients with local and operable esophageal cancer of any cell type to three cycles of preoperative 5-fluorouracil (5-FU) and cisplatin followed by surgery and two additional cycles of chemotherapy versus surgery alone. After a median follow-up of 55 months, there were no significant differences between the chemotherapy/surgery and surgery-alone groups in median survival (14.9 months and 16.1 months, respectively) or 2-year survival (35% and 37%, respectively). The addition of chemotherapy did not increase the morbidity associated with surgery. The Medical Research Council Oesophageal Cancer Working Party randomly assigned 802 patients with resectable esophageal cancer also of any cell type to two cycles of preoperative 5-FU and cisplatin followed by surgery versus surgery alone. At a median follow-up of 37 months, median survival was significantly improved in the preoperative chemotherapy arm (16.8 months vs. 13.3 months with surgery alone; difference 3.5 months; 95% CI, 1–6.5 months), as was 2-year OS (43% and 34% respectively; difference 9%; 95% CI, 3–14 months). The interpretation of the results from both of these trials is challenging because T or N staging was not reported and prerandomization and radiation could be offered at the discretion of the treating oncologist.

The Japanese Clinical Oncology Group randomly assigned 330 patients with clinical stage II or III, excluding T4, squamous cell carcinomas to receive either two cycles of preoperative cisplatin and 5-FU (fluorouracil) followed by surgery versus surgery followed by postoperative chemotherapy of the same regimen.[23][Level of evidence: 1iiC] A planned interim analysis was conducted after patient accrual, and although the primary endpoint of PFS was not met, there was a significant benefit in OS among patients treated with preoperative chemotherapy (P = .01). As a result of these findings, the Data and Safety Monitoring Committee recommended early publication.

With a median follow-up of 61 months, the 5-year OS was 55% among patients treated with preoperative chemotherapy compared with 43% among patients treated with postoperative chemotherapy (P = .04). However, there was no significant difference between groups with respect to PFS (5-year PFS, 39% vs. 44%; P = .22). Additionally, there were no significant differences between the two groups with respect to postoperative complications or treatment-related toxicities.[23] Based on these results, preoperative chemotherapy without radiation therapy should still be considered under clinical evaluation.

Two randomized trials have shown no significant OS benefit
for postoperative radiation therapy over surgery alone.[24,25][Level of evidence: 1iiA] All newly
diagnosed patients should be considered candidates for therapies and
clinical trials comparing various treatment modalities.

Information about ongoing clinical trials is available from the NCI website.

Special attention to nutritional support is indicated in any patient undergoing
treatment of esophageal cancer. (Refer to the PDQ summary on Nutrition in Cancer Care for more information.)

Stage 0 Esophageal Cancer

Stage 0 squamous esophageal cancer is rarely seen in the United States, but
surgery has been used for this stage of cancer.[1,2]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with
stage 0 esophageal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage I Esophageal Cancer

Standard treatment options:

Chemoradiation with subsequent surgery.

Surgery.

Treatment options under clinical evaluation:

Clinical trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with
stage I esophageal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage II Esophageal Cancer

Standard treatment options:

Chemoradiation with subsequent surgery.

Chemoradiation alone.

Surgery alone.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with
stage II esophageal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage III Esophageal Cancer

Standard treatment options:

Chemoradiation with subsequent surgery.

Chemoradiation alone.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with
stage III esophageal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage IV Esophageal Cancer

At diagnosis, approximately 50% of patients with esophageal cancer will have
metastatic disease and will be candidates for palliative therapy.[1]

Many agents are active in esophageal cancer. Objective response rates of 30%
to 60% and median survivals of less than 1 year are commonly reported with
platinum-based combination regimens with fluorouracil, taxanes, topoisomerase inhibitors, hydroxyurea, or vinorelbine.[1,8,9]

Clinical trials evaluating single-agent or combination chemotherapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with
stage IV esophageal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Recurrent Esophageal Cancer

All recurrent esophageal cancer patients present difficult problems in
palliation. All patients, whenever possible, should be considered candidates
for clinical trials as outlined in treatment overview.

Standard treatment options:

Palliative use of any of the standard therapies, including supportive care.

Treatment options under clinical evaluation:

Clinical trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with
recurrent esophageal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Changes to This Summary (07/08/2015)

The PDQ cancer information summaries are reviewed regularly and updated as
new information becomes available. This section describes the latest
changes made to this summary as of the date above.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of esophageal cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,

be cited with text, or

replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Esophageal Cancer Treatment are:

Jason E. Faris, MD (Massachusetts General Hospital)

Jennifer Wo, MD (Massachusetts General Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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Updated: July
8, 2015

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